parkinson's disease initial treatment of motor disorders

8/17/2019 Parkinson's Disease Initial Treatment of Motor Disorders.

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PRESCRIRE INTERNATIONAL SEPTEMBER 2015/VOLUME 24 N° 163 • PAGE 215

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Translated from Rev Prescrire April 2015; 35 (378): 286-288

Parkinson’s disease:initial treatment of motor

disorders

Parkinson’s disease is a centralnervous system disorder char-acterised by motor impairment

and various other signs and symp-toms, including neuropsychiatricdisorders (1).

The principal motor disorders aredue to gradual degeneration of dopa-minergic neurons in the brain thatare involved in carrying out move-ments. This disrupts the physiologic-al balance between dopaminergicand cholinergic neurons, the latter

becoming dominant (2,3).In Europe, the estimated preva-lence of Parkinson’s disease is about1.5% among persons over 65 yearsof age and 3.5% among those over85. Parkinson’s disease rarely occurs before age 40 (1,4,5).

A triad of motor symp-toms. Diagnosis of Parkin-son’s disease is based primar-

ily on clinical signs, especially threemotor disorders which may be more

or less severe:– Slowness and paucity of move-

ment (bradykinesia and hypokine-sia), resulting in a loss of facialexpression, loss of arm swing when

walking, and difficulty in perform-ing activities of daily living;

– Rigidity, manifested by resistanceto passive limb extension, whichoccurs in successive jerks (cog-wheel rigidity);

– Slow resting tremor occurring onmuscle relaxation (1-3).Tremor is inconsistent in early Par-

kinson’s disease. It is sometimes felt by the patient but not visible to anobserver. Symptoms are often uni-lateral, typically on the same side as

the tremor (1-3).A marked improvement in thesesymptoms soon after starting treat-ment with levodopa supports thediagnosis of Parkinson’s dis-ease (2,6).

In early-stage Parkinson’s disease,other less specific manifestationssometimes occur, including: disor-ders related to involvement of theautonomic nervous system (includ-ing orthostatic hypotension, exces-sive salivation and constipation),mood disorders (including depres-

sion and apathy), sleep disorders,pain, hallucinations or delusions.These poorly specific symptoms aresometimes present before the onsetof motor disorders (1,3,7).

● Parkinson’s disease is character-

ised by three main symptoms: slow-

ness and paucity of movements,rigidity, and resting tremor. Rapid

improvement in these symptoms

after levodopa administration sup-

ports the diagnosis of Parkinson’s

disease.

● It is important to inform the patient

tactfully, allowing him or her to con-

trol the pace at which information on

the diagnosis, symptoms and prog-

nosis is conveyed.

● Patients with minimal discomfort

or mild disability derive little benefit

from drug therapy. Physiotherapyand physical exercises are some-

times useful.

● Previously untreated patients with

marked functional impairment should

receive medication. The choice is

essentially between levodopa and

ropinirole , and mainly depends on

the patient’s age.

Key points

Not to be confused withother central nervous sys-tem disorders. The tremor

associated with Parkinson’s diseasemust be distinguished from otherdisorders, including: essential trem-or, which is often familial and occursduring activities such as writing oreating; some borderline motor defi-cits; Lewy body dementia; andsequelae of encephalitis, etc. Balanceand gait disorders are often presentin advanced-stage Parkinson’s dis-ease, but their early onset is sugges-tive of another disease (1,3,6).

Poorly known causes. Par-kinson’s disease has no clear-ly identified cause, but genet-

ic factors and brain injury might playa role. Many toxicological and epide-miological data are consistent with alink between pesticide exposure andParkinson’s disease (3,5,8).

Certain medications. Some drugs can worsen thesymptoms of Parkinson’s dis-

ease, thus reducing treatment effica-cy. Other drugs can cause or exacer- bate parkinsonian syndromes,mainly neuroleptics: antipsychoticsor “hidden” neuroleptics used asantiallergic or antiemetic medica-tion, or for migraine or sleep disor-ders. Other drugs may also beinvolved: 5-HT3-receptor antagonist(setrons), antidepressants, buspirone,trimetazidine, cholinesterase inhibi-tors used in Alzheimer’s disease, cal-cium channel blockers, valproic

acid (4).

Inform patients and pre-serve their independence. The diagnosis of Parkinson’s

disease must be conveyed tactfullyto the patient and family, taking intoaccount their prior knowledge of thedisease and their emotional reaction.The patient should first be informedof his or her existing symptoms, andthen be allowed to control the paceat which information is communi-

cated on the somewhat unpredict-able course of the disease and avail-able therapeutic options. Theexistence of support groups should be highlighted.


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R Parkinson’s disease: initial treatment of motor disorders

▲ There is no cure or treatmentcapable of slowing the progression ofParkinson’s disease. Treatment isaimed at attenuating symptoms andpreserving the patient’s indepen-dence for as long as possible. The

optimal timing of treatment initia-tion is controversial (2,3,9).

Physiotherapy and adapt-ed exercises. Patients withminimal discomfort or mild

disability derive little benefit fromdrug therapy (3).

There is some weak evidence thatphysical therapy or adapted exerciseprogrammes (brisk walking, swim-ming, etc.) may have a favourable

effect on motor disorders and quali-ty of life. The value of speech thera-py for improving articulation isuncertain (2,10).

Drug therapy for markedfunctional impairment. Patients with previously

untreated Parkinson’s disease should be offered drug therapy when thefunctional impairment becomesincapacitating. Current treatmentsare designed to enhance dopaminer-

gic activity, either with levodopa (adopamine precursor), or with anon-ergot derivative dopamine ago-nist such as ropinirole (2,3).

Levodopa: rapidly effec-tive on signs and symp-toms, but causes late-

onset motor disorders. Levodopa isthe most effective drug for treatmentof the motor symptoms of Parkin-

son’s disease. It increases speed ofmovements and reduces both stiff-ness and, to a lesser degree, tremor.All patients with Parkinson’s diseaseinitially respond to levodopa andexperience an improvement in qual-ity of life. After several years oflevodopa therapy, however, somepatients develop motor fluctuationsand dyskinesia (2,11,12).

Levodopa is administered as a fixed-dose combination with a dopa-decarboxylase inhibitor such as carbidopa

or benserazide, as this allows lowerdoses of levodopa to be used andreduces peripheral gastrointestinaland cardiac adverse effects (2,13).

Levodopa is introduced gradually,without seeking immediate or com-plete control of all symptoms. Thedose is adapted to the clinicalresponse, and the lowest effectivedose should be used (3).

The levodopa + peripheral dopa-decarboxylase inhibitor combinationis more manageable in immediate-release form than in extended-

release form (14).The adverse effect profile of levodo-

pa mainly consists of: gastrointestinaldisorders (including nausea); ortho-static hypotension and, sometimes,

hypertensive crises; psychiatricdisorders, including compulsive behaviours; daytime drowsiness(sometimes of sudden onset); abnor-mal movements; and closed-angleglaucoma (4).

Levodopa should be taken with ameal or snack to reduce nausea (9).

Drugs that decrease the effects oflevodopa include spiramycin, iron, vita-min B6 and phenytoin (4).

There is no evidence that adding adopamine agonist to levodopa earlyduring treatment improves motorsymptoms (2).

Ropinirole: for youngerpatients. Ropinirole , a

non-ergot derivative dopa-mine agonist, is less effective thanlevodopa in improving motor disor-ders but results in fewer motor fluc-tuations in the long term. Treatmentmay be started with ropinirole todelay the need for levodopa therapyand thus postpone its adverse motoreffects; this choice of initial treat-ment seems appropriate for patientsunder 65, keeping levodopa inreserve (a)(2,9).

The adverse effect profile of dopa-mine agonists mainly consists of: gas-

trointestinal disorders; hypotension(including postural hypotension);psychiatric disorders (including com-pulsive behaviours; see next section);and daytime drowsiness, sometimesof sudden onset. Unlike ergot dopa-mine agonists, ropinirole does notcause retroperitoneal or pleuropul-monary fibrosis, heart valve disease,or vasoconstriction (4).

Ropinirole interacts with drugs thatinhibit cytochrome P450 isoenzymeCYP 1A2, including fluoroquinolo-

nes and macrolides (4).

Watch out for behaviouraldisorders with dopamin-ergic drugs. Various com-

pulsive behaviours have beenreported with dopaminergic drugs,including compulsive buying orshopping, overeating and bulimia,pathological gambling, hypersexual-ity (including exhibitionism, paedo-philia and zoophilia), that can havemajor familial, social or legal reper-

cussions. It is important to informpatients and their families or carersof these risks (15,16).

©Prescrire

Drugs to avoid for initial treatmentof Parkinson’s disease

Amantadine. Amantadine is a weak dopamine agonist, which also has antimusca-

rinic effects. It has no proven efcacy when used as single-agent rst-line therapy in

Parkinson’s disease (2,4).

Monoamine oxidase type B (MAO-B) inhibitors. MAO-B inhibitors (rasagiline,

selegiline ) have only a modest impact on motor symptoms of Parkinson’s disease,

barely postponing the need for levodopa . When used early in the disease, serious

adverse effects that are disproportionate to the drugs’ limited efcacy include: psychiat-

ric disorders, cardiac arrhythmia, stroke and myocardial infarction, as well as a possible

increase in mortality. MAO-B inhibitors also increase the risk of hypertensive crises

associated with levodopa (2,4).

Rotigotine. Rotigotine is a non-ergot dopamine agonist available only in transdermal

patch form. Rotigotine seems less effective than ropinirole in Parkinson’s disease; it also

has many systemic adverse effects, as well as patch application site reactions (17).

Levodopa + entacapone. When used as rst-line treatment for Parkinson’s disease,

the combination of levodopa + entacapone , a catechol-O-methyltransferase (COMT)

inhibitor, is barely more effective than levodopa alone but causes more nausea, diarrhoea

and dyskinesia, which occur earlier and more frequently (2).

©Prescrire


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PRESCRIRE INTERNATIONAL SEPTEMBER 2015/VOLUME 24 N° 163 • PAGE 217

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a- Mid 2015 provisional results of a pragmatic ran-domised trial showed that levodopa was sligthly moreeffective than dopamine agonists on motor disorders, withmore cases of dyskinesia but less neuropsychiatric and gastrointestinal reactions. In young patients the advan-tage of using a dopamine agonist first is uncertain (RevPrescrire 2015; 35 (383): 690-691, to be translated in acoming issue).

Literature search and methodology

This review was based on data published in larevue Prescrire up to issue 374 (December 2014)and in the Prescrire Drug Interactions Guide. Addi-tional sources included the clinical pharmacologytextbook Martindale The Complete Drug Reference(www.medicinescomplete.com) and the internalmedicine website UpToDate (www.up todate.com),accessed up to 15 November 2014.

This review was prepared using the standardPrescrire methodology, which includes verifcationof the choice of documents and their analysis, andmultiple quality controls.

1- Chou KL et al. “Clinical manifestations of Par-kinson disease” UpToDate 2014.2- Prescrire Rédaction “Traitement de la maladiede Parkinson. Première partie. D’abord unemonothérapie par lévodopa ou agoniste dopami-nergique” Rev Prescrire 2011; 31 (329): 200-205.3- Prescrire Editorial Staff “Treatment of Parkin-son’s disease” Prescrire Int 1993; 2 (5): 36-39.

4- Prescrire Rédaction “12-4. Patients parkin-soniens”, “19-1-3. Profil d’effets indésirables desneuroleptiques”, “Fiche P1c. Inhibiteurs et sub-strats de l’isoenzyme CYP 1A2 du cytochromeP450” Rev Prescrire 2014; 34 (374 suppl. interac-tions médicamenteuses).5- Jankovic J et al. “Etiology and pathogenesis ofParkinson disease” UpToDate 2014.6- Chou KL et al. “Diagnosis of Parkinson disease”UpToDate 2014.7- Prescrire Editorial Staff “Treatment of Parkin-son’s disease. Psychological disorders: striking a

balance in order to optimise antiparkinsoniantreatment” Prescrire Int 2011; 20 (120): 242-245.8- Prescrire Rédaction “Pesticides et maladie deParkinson” Rev Prescrire 2013; 33 (362): 943.9- Tarsy D et al. “Pharmacologic treatment of Par-kinson disease” UpToDate 2014.

10- Tarsy D et al. “Nonpharmacologic managementof Parkinson disease” UpToDate 2014.11- Prescrire Editorial Staff “Pergolide and Parkin-son’s disease: no clear benefit” Prescrire Int 2000; 9 (50): 177-179.12- Prescrire Rédaction “Lévodopa et inhibiteur dela dopa-décarboxylase” Rev Prescrire 1989; 9 (88):339.

13- Prescrire Editorial Staff “Levodopa/carbidopacontrolled-release tablets”Prescrire Int1994;3 (12):99-101.14- Prescrire Rédaction “Traitement de la maladiede Parkinson. Deuxième partie. Réduire les fluc-tuations motrices sous lévodopa” Rev Prescrire2011; 31 (330): 273-279.15- Prescrire Rédaction “RCP des médicamentsdopaminergiques étoffés: risques de troubles com-pulsifs” Rev Prescrire 2013; 33 (354): 259.16- Prescrire Editorial Staff “Dopamine agonists:pathological gambling and hypersexuality” Pres-crire Int 2008; 17 (97): 200-201.17- Prescrire Editorial Staff “Rotigotine. Parkin-son’s disease: a step backward” Prescrire Int 2008;17 (94): 60.

Translated from Rev Prescrire April 2015; 35 (378): 282-285

Prevention of deep vein thrombosis

First choice treatments

Deep vein thrombosis is due tothe formation of a blood clot ina deep vein, usually in a lower

limb. Migration of all or part of the clotinto a pulmonary artery can result inpulmonary embolism, which can befatal despite treatment (1,2).

Prevention of pulmonary embo-lism is based on prophylaxis of deepvein thrombosis in at-risk situations,treatment of confirmed venousthrombosis, and prevention of cardi-ac embolism (3). The following arti-

cle focuses solely on the preventionof deep vein thrombosis.

Specific contexts andcontributory factors. Deep vein thrombosis and

pulmonary embolism often occur inspecific situations such as surgery,cancer, bone or spinal trauma,cardiovascular events, prolongedimmobilisation, kidney disease, andpregnancy (including the post-partum period)(3-5).

Several individual factors canincrease the risk of deep veinthrombosis, including a personalor family history of deep veinthrombosis, advanced age, obesity,

diabetes, heart failure, inflamma-tory bowel disease and thrombo-philia (3,5).

Drugs can also increasethe risk of thromboembol-ism. The following drugs are

associated with an increased risk ofdeep vein thrombosis:– Oestroprogestogens, particularly

those containing a “third-generation”progestogen (desogestrel or gestodene)

or drospirenone, and transdermalpatches containing norelgestromin;– Anti-oestrogens such as tamoxifen

and raloxifene;– Aromatase inhibitors;– Cytotoxic drugs;– Neuroleptics;– Strontium;– Corticosteroids and nonsteroidal

anti-inflammatory drugs;– Tranexamic acid (6).

Identifying high-risk

situations. The risk ofvenous thrombosis is partic-

ularly high after trauma or surgeryrequiring prolonged immobilisation,and in patients with certain medical

conditions; these situations warrantprophylaxis provided the bleedingrisk is acceptable (7).

The risk of thrombosis is particular-ly high following: hip fracture sur-gery; spinal trauma with spinal cordinjury; multiple severe trauma; hip orknee replacement surgery; majorabdominal or pelvic surgery; myocar-dial infarction treated without throm- bolysis; and stroke resulting in pro-longed immobilisation. Otherhigh-risk situations warranting anti-

thrombotic prophylaxis include treat-ment with cytotoxic drugs or withoestrogen antagonists in the postop-erative period, and hospitalisation inan intensive care unit (4,8,9).

Prophylaxis is also warranted insituations generally associated with aless elevated risk of venous thrombosisif the patient has other risk factors suchas advanced age, a personal or familyhistory of thrombosis, dehydration,cancer, obesity, acute infection, and anexacerbation of cardiac or respiratoryfailure. These situations include: pro-

longed bed rest; the period afterlengthy laparoscopic or arthroscopicsurgery; gynaecological, urological orthoracic surgery; and neurosur-gery (2,4,8,10-12).


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C o p y r i g h t o f P r e s c r i r e I n t e r n a t i o n a l i s t h e p r o p e r t y o f A s s o c i a t i o n M i e u x P r e s c r i r e ( A M P )

a n d i t s c o n t e n t m a y n o t b e c o p i e d o r e m a i l e d t o m u l t i p l e s i t e s o r p o s t e d t o a l i s t s e r v w i t h o u t

t h e c o p y r i g h t h o l d e r ' s e x p r e s s w r i t t e n p e r m i s s i o n . H o w e v e r , u s e r s m a y p r i n t , d o w n l o a d , o r

e m a i l a r t i c l e s f o r i n d i v i d u a l u s e .

parkinson's disease initial treatment of motor disorders

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